title: PNPLA3 I148M (rs738409) genetic variant and age at onset of at-risk alcohol consumption are independent risk factors for alcoholic cirrhosis.
abstract: OBJECTIVE
  Environmental and genetic factors contribute to alcoholic cirrhosis onset. In particular, age at exposure to liver stressors has been shown to be important in progression to fibrosis in hepatitis C individuals. However, no definite data on the role of age at onset of at-risk alcohol consumption are available. Moreover, patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M (rs738409) variant has been associated with alcoholic cirrhosis, but only in cross-sectional studies. The aim of this study was to investigate the role of age at onset of at-risk alcohol consumption and PNPLA3 I148M variant on alcoholic cirrhosis incidence.
  
  
  METHODS
  A total of 384 at-risk alcohol drinkers were retrospectively examined. The association among age at onset of at-risk alcohol consumption, PNPLA3 I148M variant and cirrhosis incidence was tested.
  
  
  RESULTS
  A higher incidence of alcoholic cirrhosis was observed in individuals with an older (≥24 years) compared with a younger (<24) age at onset of at-risk alcohol consumption (P-value < 0.001). Moreover, PNPLA3 148M allele carriers showed an increased incidence of cirrhosis (P-value < 0.001). Both age at onset of at-risk alcohol consumption and PNPLA3 148M allele were independent risk factors for developing cirrhosis (H.R. (95% C.I.): 2.76 (2.18-3.50), P-value < 0.001; 1.53(1.07-2.19), P-value = 0.021 respectively). The 148M allele was associated with a two-fold increased risk of cirrhosis in individuals with a younger compared with an older age at onset of at-risk alcohol consumption (H.R. (95% C.I.): 3.03(1.53-6.00) vs. 1.61(1.09-2.38).
  
  
  CONCLUSIONS
  Age at onset of at-risk alcohol consumption and PNPLA3 I148M genetic variant are independently associated with alcoholic cirrhosis incidence.
authors.affiliation: Institute of Medicine, Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Maria Antonella
authors.initials: MA
authors.lastname: Burza
authors.forename: Antonio
authors.initials: A
authors.lastname: Molinaro
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Attilia
authors.forename: Claudia
authors.initials: C
authors.lastname: Rotondo
authors.forename: Fabio
authors.initials: F
authors.lastname: Attilia
authors.forename: Mauro
authors.initials: M
authors.lastname: Ceccanti
authors.forename: Flaminia
authors.initials: F
authors.lastname: Ferri
authors.forename: Federica
authors.initials: F
authors.lastname: Maldarelli
authors.forename: Angela
authors.initials: A
authors.lastname: Maffongelli
authors.forename: Adriano
authors.initials: A
authors.lastname: De Santis
authors.forename: Adolfo Francesco
authors.initials: AF
authors.lastname: Attili
authors.forename: Stefano
authors.initials: S
authors.lastname: Romeo
authors.forename: Stefano
authors.initials: S
authors.lastname: Ginanni Corradini
mesh_terms: D000328:Adult; D017668:Age of Onset; D000428:Alcohol Drinking / Q000453:epidemiology*; D005838:Genotype; D006801:Humans; D015994:Incidence; D007558:Italy; D053208:Kaplan-Meier Estimate; D016014:Linear Models; D008049:Lipase / Q000235:genetics*; D008104:Liver Cirrhosis, Alcoholic / Q000453:epidemiology* / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008957:Models, Genetic; D020125:Mutation, Missense / Q000235:genetics*; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
keywords: Age at onset; alcohol intake; alcoholic liver disease; genetics; incidence; patatin-like phospholipase domain-containing protein 3; polymorphism